Increasing evidence suggests that dynamic changes in the transcriptional state of specific cell-types play a key role in determining disease outcomes. Here, cell-type specific changes will be detected in tuberous sclerosis complex cortical tubers and assessed if these cell-type changes are involved in the pathogenesis of epilepsy.
Tuberous sclerosis complex (TSC) is a genetic disorder that causes abnormal growths throughout the body. Almost all TSC patients present with brain abnormalities. These abnormalities are known as cortical tubers that are associated with severe epilepsy. Current treatments of the TSC associated epilepsy, such as medication or surgical resection of tubers, are often ineffective. Thus, there is an urgent need to elucidate the underlying mechanisms of TSC so that novel anti-epileptic drugs (AEDs) can be developed.
From birth, individuals with TSC require constant monitoring and individualised care. As such, TSC places a huge social and economic burden on sufferers, their primary caregivers, and health care systems. Any means that may reduce or delay the onset of seizures will significantly reduce these costs. This project (the successor of EPISTOP, see below) could lead to the development of AEDs not only for TSC, but also for other disorders associated with epilepsy. As almost 65 million people suffer from epilepsy, the societal impacts from any therapeutic development are far-reaching. The development of AEDs is hampered by the high degree of cellular heterogeneity seen in tubers which makes it difficult to ascertain the cell-types contributing to seizure development. Single nuclei RNA-Seq (snRNA-Seq) can overcome this challenge and assess gene expression changes to the level of a single cell. Here, the aim is to identify cell-based transcriptional changes that are involved in seizure development in TSC. To address this, droplet-based snRNA-Seq (DroNc-Seq) will be utilised on surgical resected tubers, uniting cutting-edge bioinformatic tools with rare human tissue.